The Scientific World Journal
Volume 2012, Article ID 202804, 5 pages
IncreasingtheStimulation Doseof rFSH inUnexpectedPoor
RespondersIs Not Associated withBetterIVF Outcome
Levent Tutuncuand OzgurDundar
IVF Unit, Department of Obstetrics and Gynecology, Haydarpasa Training Hospital, Gulhane Military Medical Academy,
Haydarpasa, 34668 Istanbul, Turkey
Correspondence should be addressed to Levent Tutuncu, firstname.lastname@example.org
Received 11 October 2011; Accepted 14 December 2011
Academic Editor: Jose G. Cecatti
Copyright © 2012 L. Tutuncu and O. Dundar. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
is associated with better in vitro fertilization (IVF) outcome or not. A total of forty eligible women who fulfilled our definition
of poor responders and who did not achieve an ongoing pregnancy in the first cycle and returned for a second higher rFSH
dose IVF cycle with a long-agonist protocol were included to the study. The first low-dose cycles and the second high-dose cycles
were compared to each other. Main outcome measures of the study were duration of stimulation, number of follicles, number of
oocytes retrieved, number of embryos, and E2 level on day of hCG injection. There were no significant differences in duration of
stimulation, number of follicles, number of oocytes retrieved, number of embryos, and E2 level on day of hCG injection between
the first low- and second high-dose cycles. Daily dose and total dose of rFSH were significantly higher in the second high-dose
cycles. Increasing the dose of rFSH in a second stimulation cycle after first unsuccessful treatment cycle will add only to the cost
and discomfort of the treatment and might adversely affect pregnancy rates.
The primary aim of in vitro fertilization (IVF) treatment is
ovarian hyperstimulation (COH) is performed by using ex-
ogenous follicle stimulating hormone (FSH) to generate as
many follicles as possible and to maximize the chances of
producing good quality embryos available for transfer. But
some patients respond poorly during COH and poor re-
sponse to COH leads to a low number of oocytes and fewer
embryos and as a result poor response associates with high
cancellation rates and low pregnancy rates. The incidence of
poor response to COH has been reported between 9% and
The starting daily dose of gonadotrophin is generally
ponse to prior stimulation protocols. At present the ideal
stimulation regimen for poor responders is not known and
age may not be an important factor . It is generally be-
lieved that older and poor responder patients require higher
doses to overcome the decline in ovarian response. But this
practice is based on empirical evidence rather than on sound
evidence . Although increasing doses of gonadotrophins
have been shown to increase the number of collected oocytes
, later this improvement was explained by a phenomenon
FSH above a threshold dose had not been found valuable ,
even if it may have adverse implications on pregnancy rates
. Moreover, it has been shown that an unexpected poor
response in a young patient in the first IVF cycle was not
necessarily related to a poor prognosis in subsequent cycles
. Ovarian sensitivity for gonadotrophins varies among
women, and an individualized approach is most likely to
result in a sufficient number of oocytes with minimal side
The objective of this study is to observe the second high-
er gonadotrophin dose IVF outcomein unexpected poor res-
ponder patients. In particular we investigated if a high daily
dose of rFSH in poor responders is associated with higher
number of oocytes at the time of retrieval and improved
2The Scientific World Journal
Table 1: Baseline information on the characteristics of women and regimens.
Basal FSH (mIU/mL) on day 3a
Treatment duration (days)a
E2 level on day of HCG (pg/mL)a
Total rFSH dose (IU)a
rFSH dose (IU) per stimulation daya
aValues are mean ± SD
NS = Not significant.
First cycle (low dose)
Second cycle (high dose)
P < 0.05
P < 0.05
pregnancy rate. We analyzed retrospectively IVF data from
May 2007 to May 2011 for patients who had at least two
cycles of stimulation with rFSH and a higher dose in second
cycle because of an unexpected poor response in the first
We reviewed IVF cycles performed at the Gulhane Military
Medical Academy, Haydarpasa Training Hospital IVF Unit,
from May 2007 to May 2011 retrospectively. Patient charts
were reviewed and the following data recorded: age, body
mass index (BMI), cause of infertility, basal day 3 serum
FSH value, total amount of rFSH dose in IU used during
the stimulation, cycle length, E2 serum value on day of
hCG, number of follicles ≥ 17mm on day of hCG, num-
ber of oocytes retrieved, and number of transferable embry-
os. General medical and gynecological histories were record-
ed together with the result of physical examination and lab-
Patients were included in the study if they had completed
a stimulation protocol with rFSH (Gonal-F, Merck Serono,
Turkey, or Puregon, Schering-Plough, Turkey) and fulfilled
our standard definition of poor responders and who did not
achieve an ongoing pregnancy in the first cycle and who
returned for a second higher-dose IVF cycle. Although dif-
ferent criteria were used in various published studies and
lack a uniform definition of poor response, we defined poor
responders as patients with less than 4 mature oocytes re-
trieved and less than or equal to 3 follicles and/or Estradiol
(E2) levels of less than 500pg/mL on the day of hCG
administration. ESHRE recently presented “a consensus
paper” to standardize the definition of poor response and
they proposed similar criteria . All patients who were
eligible for the study agreed to participate and each patient
provided their written informed consent.
All patients started with 150–225IU per day with rFSH
s.c. injection on the first cycle (first low-dose cycle) and 225–
375IU per day in a consecutive next cycle (second high-dose
cycle). The second high-dose stimulation cycle was within 1
year after first low-dose stimulation cycle. Other inclusion
criteria include the following: age < 40 years and BMI ≤
29kg/m2or >18kg/m2, FSH ≤ 12IU/L, regular spontaneous
menstrual cycle (24–35 days) and presence of two ovaries.
Pretreatment with leuprolide acetate (Lucrin; Abbott,
Turkey) for pituitary downregulation was started in the mid-
luteal phase and when downregulation was achieved (E2 ≤
50pg/mL) after menstruation, treatment with rFSH was
started and continued until at least three follicles ≥ 17mm
had developed. Human chorionic Gonadotrophin (hCG)
(Pregnyl, Schering-Plough, Turkey) 10,000IUi.m. or rhCG
(Ovitrelle, Merck Serono, Turkey) 250mcg.s.c. was used to
trigger ovulation for each cycle. Serum concentrations of
(E2), FSH, and LH were measured at baseline and E2 and
progesterone on the day of hCG injection. Monitorization
of the cycle was done with vaginal ultrasound and E2 mea-
surements. Oocyte retrieval was performed transvaginally
under ultrasound guidance after 35 hours of hCG injection.
The number of follicles aspirated and oocytes retrieved was
recorded during aspiration. Standard IVF and ICSI proce-
dures were used depending on sperm quality. Evidence for
fertilization was assessed approximately 16–18 hours after
IVF or ICSI. Luteal support was provided by vaginal progest-
erone gel (Crinone, Merck Serono, Turkey).
We compared the first low-dose cycles with the second
high-dose cycles. Parameters compared include daily and
total dose of rFSH, duration of stimulation, number of fol-
licles, number of oocytes retrieved, number of embryos, and
E2 level on day of hCG injection. Each patient functioned as
her own control.
Statistical analyses were performed using the Statistical
Package for the Social Sciences, version 16.0 for Windows
(SPSS, Inc., Chicago, IL USA). The statistical analysis was
done with the Student’s t-test and Chi-Square test. A P value
of < 0.05 was considered to be statistically significant.
Forty patients were eligible and identified in this retrospec-
tive study. The causes of infertility in the patients were male
infertility (22.5%), tubal infertility (22.5%), endometriosis
(17.5%), and unexplained (37.5%).
Table 1 presents the overall patient and cycle character-
istics. Patient characteristics were similar in each first low-
dose and second high-dose cycle. Patients were one year
older at the time of the second high-dose cycle (34.35 ± 3.88
years versus 35 ± 3.70 years), but this was not significantly
different (P ≥ 0.05). Mean E2 level on day of hCG was
The Scientific World Journal3
Table 2: Comparison of two consecutive cycles which dose of rFSH
has been increased.
Number of aspirated
Number of oocytes
Fertilization rate (%)
Number of transferable
aValues are mean ± SD
NS = Not significant.
2.30 ±0.642.375 ±0.66NS
12/40 = 30%
5/40 = 12.5%
P < 0.05
711.8 ± 278.4pg/mL and 822.42 ± 311.2pg/mL in first low-
was no significant difference (P ≥ 0.05).
At first low-dose cycle 70% of the patients had oocyte
retrieval and 55% had embryo transfer. On the other hand at
second high-dose cycle oocyte retrieval and embryo transfer
cycle (87.5% and 62.5%, resp.) (P < 0.05). But the outcome
measures were not different between the first low-dose cycle
and second high-dose cycle (Table 2). Patients showed no
versus 2.375 ± 0.66) and mean number of oocytes retrieved
(1.40 ± 1.15 versus 1.50 ± 0.877) (P ≥ 0.05). Upward FSH
dose adjustment did not produce any significant increase in
the mean number of transferable embryos per cycle (0.775±
0.8 versus 0.85 ± 0.8, P ≥ 0.05). Fertilization rates were
similar in the first low-dose cycle and second high-dose cycle
(55.3% and 56.6%, resp.) (P ≥ 0.05).
Cycle lengths were similar in the 2 groups (11.45 ± 1.67
days versus 11.7 ± 1.11 days). But rFSH dose (IU) per
stimulation day (176.25±36.22IU versus 285.00±59.32IU)
and the total dose of gonadotrophins used (2018.06 ±
557.6IU versus 3334.5 ± 643.2IU) were significantly higher
in the second high-dose cycle group compared with the first
low-dose group (P < 0.05), with higher cost in the second
More cycles were cancelled during the low-dose stimula-
tion protocol (12/40 = 30% versus 5/40 = 12.5%, P < 0.05).
We did not analyze the pregnancy rates on the first low-dose
cycle because the patients who become pregnant after first
cycle were not included in the study. However there were
only 2 pregnancies after second high dose cycle. Ongoing
pregnancy rate in the second high-dose cycle was only 5%.
Compared to a historic normal responder control group this
represents a very low percentage (data not shown).
There was no ovarian hyperstimulation or hospitaliza-
tion for any other reason during the treatment period.
In this retrospective study we demonstrated that increasing
response in the first IVF cycle reduces the cancellation rate.
Besides it may increase the oocyte retrieval rates and embryo
transfer rates. But increasing the dose of gonadotrophin in a
second cycle after the first unexpected poor response did not
increase the number of oocytes retrieved and the number of
A generally accepted practice in IVF is to increase the
daily dose of gonadotrophins if the first treatment cycle
is unsuccessful. This is done with the belief that a higher
gonadotrophin dose will stimulate a somehow compromised
ovary to a better response, assuming a dose response rela-
and number of follicles. But if this relationship is true for
good responders, the situation is physiologically different
in poor responders. This study gives empirical evidence
to this statement. The ovary of poor responders (although
with a normal FSH levels) is less responsive to exogenous
gonadotrophins. This underlines the poor predictive value of
day 3 FSH in this subgroup of patients and it suggests that
there may be other reasons than reduced ovarian reserve for
a poor response.
During ovulation induction for assisted reproductive
technologies, increasing the number of oocytes collected can
allow better embryo selection and maybe better pregnancy
rates . Several authors analyzed the effect of increasing
the gonadotrophins stimulation dose to poor responders.
Initial studies were performed with purified urinary FSH. In
1989, Hofmann et al. showed that ovarian hyperstimulation
with high doses of FSH may result improved E2 response
and fewer cancellations in poor responder patients, and they
suggested that high-dose FSH may offer a good alternative
for these patients . But only one year later in another
study from the same center, Karande et al. concluded that
high-dose FSH stimulation at the onset of the menstrual
cycle does not improve the IVF outcome in low-responder
patients . Land et al. doubled the FSH dose in the
second cycle to improve the outcome in poor responders
. They reported a significant increase in the number of
oocytes but not in the number of embryos. Lashen et al.
 conducted a retrospective study and reported that
low- and average-responder patients but not high-responder
patients had significantly higher numbers of eggs, embryos,
and higher E2 levels in their second cycles in which the
dose of gonadotrophin was increased. But they found that
there was no difference for the pregnancy rate between the
groups although there were differences for other parameters.
this preparation. They found that increasing the FSH dose
above 300IU/day after a poor response in the first cycle is
pointless. However, Pantos et al. showed that increasing the
gonadotrophin dose above 150IU/day did not increase the
number of oocytes in poor responders . In a prospective
randomized trial of Garcia-Velasco et al., early cessation of
GnRHa combined with high doses of gonadotrophins had
recruited a significantly higher number of mature oocytes
a conventional nonstop, long downregulation protocol .
More recent studies analyzed the same questions using
rFSH. Studies comparing different doses of rFSH suggest
4 The Scientific World Journal
that pregnancy rates do not increase with increasing doses
of rFSH. Two different randomized double-blind clinical
trials are analyzed if a higher-dose protocol is associated
with better outcome. Fixed daily doses of recombinant FSH
(rFSH) (100 versus 200IU) resulted in higher number
of oocytes at the time of the retrieval in the high-dose
group, but the clinical pregnancy rates were the same and
more sideeffects were noted with the high-dose regimen
[17, 18]. Another study showed that an increase in rFSH
daily dose from 150IU to 250IU did not result in a higher
number of retrievable oocytes in older women . In a
American Puregon study concluded that an increase in the
daily recombinant FSH dose from 150 to 250IU in women
between 30 and 39 years of age has only limited benefit, and
the clinical use of these higher doses can be questioned .
The main difference between these trials [17–20] and our
study is that we followed the same group of patients in a
second high-dose cycle; therefore each patient functioned as
her own control.
In a systematic review, Tarlatzis et al.  showed that
the results of the trials were controversial, and there is no
in poor responders. In a prospective randomized controlled
study, expected poor responders on the basis of an antral
follicle count did not benefit from a higher starting dose of
gonadotrophins in IVF treatment with a daily dosage of
300IU of recombinant FSH when compared with 150IU
. Lekamge et al.  reported the same findings in a
retrospective study. Our results are very similar with these
studies. Siristatidis and Hamilton  had evaluated the
clinical trials about the effectiveness of the high dose FSH
regimes and tried to find out the safest and most effective
upper limit of FSH that might be used for COH in poor
responders. They concluded that most of the retrospective
studies and reviews had showed that to increase the dose
was useless. But their comments about some prospective
randomized trials were quite interesting, because they had
given particulars a satisfactory ovarian response and preg-
nancy rate would achieved when the FSH dose exceed
the 300IU dosage, being combined with various types
of downregulation or adjuvant strategies. A recent meta-
analysis suggested that the optimal daily rFSH stimulation
dose is 150IU/day in presumed normal responders younger
than 39 years undergoing IVF . In this study the average
number of oocytes retrieved per pick-up was increased when
higher rFSH doses over 100IU/day were given, whereas
pregnancy rates did not differ across the dosage range tested
and cumulative pregnancy rates including additional cryo
embryo transfer cycles would not become superior with
dosages exceeding 150IU/day. The conclusion of this meta-
analysis was when using 150IU/day the probability of poor
response was not different from higher dosages, indicating
that 150IU/day is likely to represent the optimal dosage in
higher daily, and total rFSH doses in the second treatment
cycles, the numbers of follicles, the number of oocytes
retrieved and total number of transferable embryos were all
similar in both the low-dose and high-dose treatment cycles.
Nowadays, mild ovarian stimulation protocols for IVF
are being developed in order to reduce the cost and to
minimize the complications of COH. Other benefits of
mild stimulation might be the probability of generating
better embryos and more receptive endometrium because of
the potentially negative effects of supraphysiological steroid
levels on oocyte quality and endometrial receptivity .
Although the usual mild stimulation protocol is held with
GnRH antagonists, mild IVF using GnRHa long protocol is
possible too . But, mild ovarian stimulation has not yet
been tested in the context of ovarian aging . After mild
ovarian stimulation, a modest number of oocytes are asso-
ciated with optimal implantation rates and do not reflect a
poor ovarian response . When we evaluate and compare
our results with these data about mild ovarian stimulation,
increasing the dose of rFSH in a second stimulation cycle
after first unsuccessful treatment cycle will add only to the
The results of our study indicate that increasing the starting
dose of gonadotrophin after an unexpected poor response
in the first IVF cycle is not an effective approach. It may
increase the oocyte retrieval rates and embryo transfer rates
but will not add any significant improvement in the number
The only important benefit of increasing the dose was the
low cancellation rate. There is no linear relationship between
the dose of recombinant FSH and the ovarian response in
unexpected poor responders.
Conflict of Interests
The authors declare that they have no conflict of interests.
 D. Kyrou, E. M. Kolibianakis, C. A. Venetis, E. G. Papaniko-
laou, J. Bontis, and B. C. Tarlatzis, “How to improve the prob-
ability of pregnancy in poor responders undergoing in vitro
fertilization: a systematic review and meta-analysis,” Fertility
and Sterility, vol. 91, no. 3, pp. 749–766, 2009.
 B. Vollenhoven, T. Osianlis, and J. Catt, “Is there an ideal
stimulation regimen for IVF for poor responders and does it
change with age?” Journal of Assisted Reproduction and Genet-
ics, vol. 25, no. 11-12, pp. 523–529, 2008.
 M. H. A. Van Hooff, “The human menopausal gonadotropin
(hMG) dose in in vitro fertilization (IVF): what is the optimal
dose?” Journal of Assisted Reproduction and Genetics, vol. 12,
no. 4, pp. 233–235, 1995.
 H. Lashen, W. Ledger, Bernal A. L´ opez, B. Evans, and D.
Barlow, “Superovulation with a high gonadotrophin dose for
in vitro fertilization: is it effective?” Journal of Assisted Repro-
duction and Genetics, vol. 15, no. 7, pp. 438–443, 1998.
 L. Rombauts, “Is there a recommended maximum starting
dose of FSH in IVF?” Journal of Assisted Reproduction and Ge-
netics, vol. 24, no. 8, pp. 343–349, 2007.
The Scientific World Journal5 Download full-text
 D. N. Lekamge, M. Lane, R. B. Gilchrist, and K. P. Tremellen,
“Increased gonadotrophin stimulation does not improve IVF
outcomes in patients with predicted poor ovarian reserve,”
Journal of Assisted Reproduction and Genetics, vol. 25, no. 11-
12, pp. 515–521, 2008.
 L. Pal, S. Jindal, B. R. Witt, and N. Santoro, “Less is more:
increased gonadotropin use for ovarian stimulation adversely
influences clinical pregnancy and live birth after in vitro fer-
tilization,” Fertility and Sterility, vol. 89, no. 6, pp. 1694–1701,
 E. R. Klinkert, F. J. M. Broekmans, C. W. N. Looman, and E. R.
is not necessarily related to a poor prognosis in subsequent
cycles,” Fertility and Sterility, vol. 81, no. 5, pp. 1247–1253,
 B. Popovic-Todorovic, A. Loft, S. Ziebe, and A. Nyboe An-
dersen, “Impact of recombinant FSH dose adjustments on
ovarian response in the second treatment cycle with IVF or
first cycle,” Acta Obstetricia et Gynecologica Scandinavica, vol.
83, no. 9, pp. 842–849, 2004.
 A. P. Ferraretti, A. La Marca, B. C. J. M. Fauser, B. Tarlatzis,
G. Nargund, and L. Gianaroli, “ESHRE consensus on the def-
inition of “poor response” to ovarian stimulation for in vitro
fertilization: the Bologna criteria,” Human Reproduction, vol.
26, no. 7, pp. 1616–1624, 2011.
 N. S. Macklon, R. L. Stouffer, L. C. Giudice, and B. C. J. M.
Fauser, “The science behind 25 years of ovarian stimulation
for in vitro fertilization,” Endocrine Reviews, vol. 27, no. 2, pp.
 G. E. Hofmann, J. P. Toner, S. J. Muasher, and G. S. Jones,
“High-dose follicle-stimulating hormone (FSH) ovarian stim-
ulation in low-responder patients for in vitro fertilization,”
Journal of In Vitro Fertilization and Embryo Transfer, vol. 6, no.
5, pp. 285–289, 1989.
 V. C. Karande, G. S. Jones, L. L. Veeck, and S. J. Muasher,
“High-dose follicle-stimulating hormone stimulation at the
onset of the menstrual cycle does not improve the in vitro
fertilization outcome in low-responder patients,” Fertility and
Sterility, vol. 53, no. 3, pp. 486–489, 1990.
 J. A. Land, M. I. Yarmolinskaya, J. C. M. Dumoulin, and J. L.
H. Evers, “High-dose human menopausal gonadotropin stim-
ulation in poor responders does not improve in vitro fertiliza-
tion outcome,” Fertility and Sterility, vol. 65, no. 5, pp. 961–
 C. Pantos, S. J. Thornton, A. L. Speirs, and I. Johnston, “In-
creasing the human menopausal gonadotropin dose - does the
response really improve?” Fertility and Sterility, vol. 53, no. 3,
pp. 436–439, 1990.
 J. A. Garcia-Velasco, V. Isaza, A. Requena et al., “High doses of
gonadotrophins combined with stop versus non-stop protocol
of GnRH analogue administration in low responder IVF pa-
tients: a prospective, randomized, controlled trial,” Human
Reproduction, vol. 15, no. 11, pp. 2292–2296, 2000.
 H. J. Out, S. Lindenberg, A. L. Mikkelsen et al., “A prospective,
randomized, double-blind clinical trial to study the efficacy
and efficiency of a fixed dose of recombinant follicle stimulat-
ing hormone (Puregon(TM)) in women undergoing ovarian
 H. J. Out, I. David, R. Ron-El et al., “A randomized, double-
blind clinical trial using fixed daily doses of 100 or 200 IU of
recombinant FSH in ICSI cycles,” Human Reproduction, vol.
16, no. 6, pp. 1104–1109, 2001.
 H. J. Out, D. D. M. Braat, B. M. E. Lintsen, T. Gurkan, O.
Bukulmez, O. Gokmen et al., “Increasing the daily dose of
recombinant follicle stimulating hormone (puregon) does not
compensate for age-related decline in retrievable oocytes after
controlled ovarian hyperstimulation,” Human Reproduction,
vol. 15, pp. 29–35, 2000.
dose of 150 and 250 IU of recombinant follicle-stimulating
hormone in women undergoing in vitro fertilization,” Fertility
and Sterility, vol. 76, no. 5, pp. 950–956, 2001.
 B. C. Tarlatzis, L. Zepiridis, G. Grimbizis, and J. Bontis,
“Clinical management of low ovarian response to stimulation
for IVF: a systematic review,” Human Reproduction Update,
vol. 9, no. 1, pp. 61–76, 2003.
 E. R. Klinkert, F. J. M. Broekmans, C. W. N. Looman, J. D.
F. Habbema, and E. R. te Velde, “Expected poor responders
on the basis of an antral follicle count do not benefit from a
higher starting dose of gonadotrophins in IVF treatment: a
randomized controlled trial,” Human Reproduction, vol. 20,
no. 3, pp. 611–615, 2005.
 C. S. Siristatidis and M. P. Hamilton, “What should be the
maximum FSH dose in IVF/ICSI in poor responders?” Journal
 M. D. Sterrenburg, S. M. Veltman-Verhulst, M. J.C. Eijkemans
in vitro fertilization in presumed normal responders younger
than 39 years: a meta-analysis,” Human Reproduction Update,
vol. 17, no. 2, pp. 184–196, 2011.
ian stimulation for IVF,” Human Reproduction Update, vol. 15,
no. 1, pp. 13–29, 2009.
 S. Fern´ andez-Shaw, N. P´ erez Esturo, R. Cercas Duque, and I.
Pons Mallol, “Mild IVF using GnRH agonist long protocol
is possible: comparing stimulations with 100 IU vs. 150IU
recombinant FSH as starting dose,” Journal of Assisted Repro-
duction and Genetics, vol. 26, no. 2-3, pp. 75–82, 2009.
 B. C. J. M. Fauser, G. Nargund, A. N. Andersen et al., “Mild
ovarian stimulation for IVF: 10 years later,” Human Reproduc-
tion, vol. 25, no. 11, pp. 2678–2684, 2010.
clinical significance of the retrieval of a low number of oocytes
following mild ovarian stimulation for IVF: a meta-analysis,”
Human Reproduction Update, vol. 15, no. 1, pp. 5–12, 2009.